Papillomaviruses are small DNA viruses that induce persistent epithelial lesions, known as warts or papillomas, and in some cases these lesions can progress to malignant carcinomas. The E2 proteins are required for transcriptional transactivation and repression, initiation of DNA replication and stable episomal maintenance of viral genomes. We have shown that papillomavirus genomes and the E2 transactivator protein interact with cellular mitotic chromosomes in dividing cells and we are studying the details of this interaction. This ensures that viral genomes are properly segregated to daughter cells. We have shown that the E2 proteins are phosphorylated and are studying whether phosphorylation regulates E2 protein stability and genome copy number.In most cervical cancers, papillomavirus DNA is found integrated into cellular chromosomes instead of replicating episomally. This disrupts the E1 and/or E2 regulatory genes and is a critical step in malignant progression. We have developed a system to immortalize primary human keratinocyte cells containing hybrid papillomavirus genomes that are maintained episomally in the absence of E1 and E2. This system is being used to determine the role of the E1 and E2 regulatory functions in keratinocyte growth and differentiation. - Papillomavirus, DNA replication, transcription, virology, cancer, gene transfer